The invention relates to novel tryptase inhibitors which are used in the pharmaceutical industry for preparing medicaments.
The international applications WO95/32945, WO96/09297, WO98/04537, WO99/12918 and WO99/24395 describe low-molecular-weight compounds for use as tryptase inhibitors.
It has now been found that the compounds of the formula I, which are described in more detail below, have surprising and particularly advantageous properties.
The invention provides compounds of the formula I 
in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur), xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group consisting of 
where
E is xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur) or xe2x80x94CH2xe2x80x94 (methylene),
G is xe2x80x94Oxe2x80x94 (oxygen) or xe2x80x94CH2xe2x80x94 (methylene), and
T is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94 or a bond,
M is the following central building block 
K1 is xe2x80x94B7-(C(O))mxe2x80x94B9-X1, xe2x80x94B7-(C(O))mxe2x80x94B9-Y1 or xe2x80x94B7-(C(O))mxe2x80x94B9-Z1-B11-X1,
K2 is xe2x80x94B8-(C(O))pxe2x80x94B10-X2, xe2x80x94B8-(C(O))pxe2x80x94B10-Y2 or xe2x80x94B8-(C(O))pxe2x80x94B10-Z2-B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-4C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are identical or different and are selected from the following groups 
where
R8 is 1-4C-alkyl,
Y1 and Y2 are identical or different and are a 4-11C-heteroaryl or 2-7C-heterocycloalkyl radical containing at least one ring nitrogen,
Z1 and Z2 are identical or different and are 5-12C-arylene, 5-12C-heteroarylene, 3-8C-cycloalkylene 3-8C-heterocycloalkylene,
where each arylene, heteroarylene, cycloalkylene, heterocycloalkylene, heteroaryl or heterocycloalkyl may additionally for its part be substituted by one, two or three substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,
and where on the direct route between the terminal nitrogen atoms 20 to 40, preferably 25 to 40, bonds have to be present,
the salts of these compounds, and the N-oxides of the nitrogen-containing heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes, and their salts, where all those compounds are excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 may assume the meaning of a bond resulting in the direct linkage of two heteroatoms or two carbonyl groups.
1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radicals.
1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
1-4C-Alkoxycarbonyl represents a carbonyl group to which is attached one of the above-mentioned 1-4C-alkoxy radicals. Examples which may be mentioned are the methoxycarbonyl [CH3Oxe2x80x94C(O)xe2x80x94] and the ethoxycarbonyl [CH3CH2Oxe2x80x94C(O)xe2x80x94] radicals.
1-4C-Alkylcarbonyloxy represents a carbonyloxy group to which is attached one of the above-mentioned 1-4C-alkyl radicals. An example which may be mentioned is the acetoxy [CH3C(O)xe2x80x94Oxe2x80x94] radical.
For the purpose of the invention, halogen is bromine, chlorine and fluorine.
1-4C-Alkylene represents straight-chain or branched 1-4C-alkylene radicals, for example the methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94), trimethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94), tetramethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94), 1,2-dimethylethylene [xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94], 1,1-dimethylethylene [xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94], 2,2-dimethylethylene [xe2x80x94CH2xe2x80x94C(CH3)2xe2x80x94], isopropylidene [xe2x80x94C(CH3)2xe2x80x94] or the 1-methylethylene [xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94] radicals.
If m is 0, the group xe2x80x94(C(O))mxe2x80x94 is a bond.
If p is 0, the group xe2x80x94(C(O))pxe2x80x94 is a bond.
4-11C-Heteroaryl represents axe2x80x94if desired substitutedxe2x80x94mono- or bicyclic aromatic hydrocarbon which contains 4 to 11 carbon atoms and at least one ring nitrogen atom; in addition, one or more of the carbon atoms may be replaced by ring heteroatoms selected from the group consisting of O, N and S. In the case of bicycles, at least one of the rings is aromatic. Examples which may be mentioned are pyrid-4-yl, pyrid-3-yl, pyrimidin-5-yl, imidazol-1-yl and benzimidazol-5-yl.
2-7C-Heterocycloalkyl represents axe2x80x94if desired substitutedxe2x80x94monocyclic saturated or partially saturated hydrocarbon which contains 2 to 7 carbon atoms and at least one ring nitrogen atom; in addition, one or more carbon atoms may be replaced by ring heteroatoms selected from the group consisting of O, N and S. Examples which may be mentioned are piperid4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, lmidazolidin-4-yl and morpholin-2-yl.
5-12C-Arylene represents axe2x80x94if desired substitutedxe2x80x94divalent mono- or bicyclic aromatic hydrocarbon radical having 5 to 12 carbon atoms, where in the case of bicyclic aromatic hydrocarbon radicals at least one of the rings is aromatic. The free valencies can both be located at the aromatic, both at the nonaromatic or one at the aromatic and one at the nonaromatic ring. Examples which may be mentioned are 1,4-phenylene, 1,3-phenylene, 1,4-naphthylene and 2,6-naphthylene.
5-12C-Heteroarylene represents an arylene radical as defined above in which 1 to 4 carbon atoms are replaced by heteroatoms selected from the group consisting of O, N and S. Examples which may be mentioned are 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene, 5,2-pyridylene, 2,5-indolylene, 2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene, 3,6-indazolylene, 2,5-benzofuranylene, 2,6-quinolinylene and 4,2-thiazolylene.
3-8C-Cycloalkylene represents axe2x80x94if desired substitutedxe2x80x94divalent monocyclic saturated or partially saturated hydrocarbon radical having 3 to 8 carbon atoms. Examples which may be mentioned are the 1,3-cyclopentylene, the 1,3-cyclohexylene and preferably the 1,4-cyclohexylene radicals.
3-8C-Heterocycloalkylene represents a cycloalkylene radical as defined above in which 1 to 3 carbon atoms are replaced by heteroatoms selected from the group consisting of O, N and S. Examples which may be mentioned are the 1,4-piperidinylene, 1,4-piperazinylene, 2,5-pyrrolidinylene, 4,2-imidazolidinylene and preferably the 4,1-piperidinylene radicals.
Preferred meanings of the groups X1 and X2 are amino, aminocarbonyl, amidino and guanidino.
By definition, the groups Z1 and Z2 are located between the groups B9 and B11 (xe2x80x94B9-Z1-B11-) and B10 and B12 (xe2x80x94B10-Z2-B12-), respectively. Accordingly, in the divalent groupings mentioned by way of example (for example 2,6-indolylene), the first number indicates the point of attachment to the group B9 and B10, respectively, and the second number indicates the point of attachment to the group B11 and B12, respectively.
The definitions of M, A3, A4, X1 and X2 contain chemical formulae, such as, for example, 
Here, bonds which are unattached on one side mean that the building block is attached at this site to the remainder of the molecule. Bonds which are unattached on both sides mean that this building block has a plurality of sites via which the building block can be attached to the remainder of the molecule.
In the context of this application, the term terminal nitrogen atom means in each case a nitrogen atom in the groups designated X1, X2, Y1 and Y2.
If the group X1 or X2 contains only one nitrogen atom, this nitrogen atom is the terminal nitrogen atom.
If the group X1 or X2 contains a plurality of nitrogen atoms, the nitrogen atom which is furthest from the atom by means of which the bond to the group B9 (B11) or B10 (B12) is established is the terminal nitrogen atom.
If the group Y1 or Y2 contains only one ring nitrogen atom, this ring nitrogen atom is the terminal nitrogen atom.
If the group Y1 or Y2 contains a plurality of ring nitrogen atoms, the ring nitrogen atom which is furthest from the atom by means of which the bond to the group B9 or B10 is established is the terminal nitrogen atom.
According to the invention, the direct route between the nitrogen atoms which act as terminal nitrogen atoms in the groups defined as X1 (Y1) or X2 (Y2) is considered to be the number of bonds which is obtained by counting the bonds which represent the shortest possible connection between the terminal nitrogen atoms.
The following example is meant to illustrate the determination of the number of bonds on the direct route between two terminal nitrogen atoms: 
Here, the direct route comprises 34 bonds.
Suitable salts for compounds of the formula Ixe2x80x94depending on substitutionxe2x80x94are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically acceptable salts of inorganic and organic acids customarily used in pharmacy. Those suitable are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are employed in salt preparationxe2x80x94depending on whether a mono- or polybasic acid is concerned and depending on which salt is desiredxe2x80x94in an equimolar quantitative ratio or one differing therefrom.
On the other hand, salts with bases are also suitable. Examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, where here too the bases are employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically unacceptable salts which can be obtained initially as process products, for example in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention, and also their salts, may contain varying amounts of solvents, for example when they are isolated in crystalline form. The invention therefore also embraces all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
Compounds of the formula I which are to be emphasized are those in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or a bond, or are selected from the group consisting of 
where
E is xe2x80x94Oxe2x80x94 (oxygen), xe2x80x94Sxe2x80x94 (sulfur) or xe2x80x94CH2xe2x80x94 (methylene) and
T is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are Identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94 or a bond,
M is the following central building block 
K1 is xe2x80x94B7-(C(O))mxe2x80x94B9-X1, xe2x80x94B7-(C(O))mxe2x80x94B9-Y1 or xe2x80x94B7-(C(O))mxe2x80x94B9-Z1-B11-X1.
K2 is xe2x80x94B8-(C(O))pxe2x80x94B10-X2, xe2x80x94B8-(C(O))pxe2x80x94B10-Y2 or xe2x80x94B8-(C(O))pxe2x80x94B10-Z2xe2x80x94B12-X2,
B1, B2, B3, B4, B5 and B6 are identical or different and are a bond or 1-4C-alkylene,
B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1-4C-alkylene,
m is 0 or 1,
p is 0 or 1,
X1 and X2 are Identical or different and are selected from the following groups 
where
RB is 1-4C-alkyl,
Y1 and Y2 are identical or different and are piperid-4-yl, piperid-3-yl, piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, 2-imidazolin-3-yl, 2-imidazolin-2-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, pyrid-4-yl, pyrid-3-yl, pyridazin-4-yl, pyrimidin-5-yl, pyrimidin-4-yl, indol-3-yl, benzimidazol-4-yl or benzimidazol-5-yl,
Z1 and Z2 are identical or different and are 1,4-phenylene, 1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-cyclohexylene, 1,3-cyclohexylene, 1,3-cyclopentylene, 1,4-piperazinylene, 4,1-piperidinylene, 1,4-piperidinylene, 2,5-pyrrolidinylene, 4,2-imidazolidinylene, 2,5-furylene, 2,5-pyrrolylene, 4,2-pyridylene, 5,2-pyridylene, 2,5-indolylene, 2,6-indolylene, 3,5-indolylene, 3,6-indolylene, 3,5-indazolylene, 3,6-indazolylene, 2,6-quinolinylene, 2,5-benzofuranylene or 4,2-thiazolylene,
where each arylene, heteroarylene, cycloalkylene, heterocycloalkylene, heteroaryl or heterocycloalkyl may additionally for its part be substituted by one, two or three substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, amino, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, carboxyl or aminocarbonyl,
and where on the direct route between the terminal nitrogen atoms 20 to 40, preferably 25 to 40, bonds have to be present,
the salts of these compounds, and the N-oxides of the nitrogen-containing heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes, and their salts, where all those compounds are excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or may assume the meaning of a bond, resulting in the direct linkage of two heteroatoms or carbonyl groups.
One embodiment of the compounds of the formula I which are to be emphasized is that in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94C(O)xe2x80x94 or a bond,
A3 and A4 are identical or different and are selected from the group consisting of 
where
T is the group xe2x80x94C(O)xe2x80x94 or a bond,
A5 and A6 are identical or different and are xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94,
M is the following central building block 
K1 is xe2x80x94B7-(C(O))mxe2x80x94B9-Y1 or xe2x80x94B7-(C(O))mxe2x80x94B9-Z1-B11-X1,
K2 is xe2x80x94B8-(C(O))pxe2x80x94B10-Y2 or xe2x80x94B8-(C(O))pxe2x80x94B10-Z2-B12-X2,
B1 and B2 are identical or different and are a bond or methylene,
B3, B4, B5 and B6 are identical or different and are a bond or 1-3C-alkylene,
B7, B8, B9 and B10 are identical or different and are a bond or 1-4C-alkylene,
B11 and B12 are identical or different and are a bond or methylene,
m is 0,
p is 0,
X1 and X2 are identical or different and are selected from the following groups 
Y1 and Y2 are imidazol-1-yl,
Z1 and Z2 are identical or different and are 5,2-pyridinylene, 6-methyl-5,2-pyridinylene, 4,1-piperidinylene, 3,6-indazolylene, 3,6-indolylene, 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or 1,4-cyclohexylene,
and where on the direct route between the terminal nitrogen atoms 20 to 40, preferably 25 to 40, bonds have to be present,
the salts of these compounds, and the N-oxides of nitrogen-containing heteroaryls, heteroarylenes and heterocycloalkylenes, and their salts, where all those compounds are excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 may assume bond, resulting in the direct linkage of two heteroatoms or carbonyl groups.
Another embodiment of the compounds of the formula I which are to be emphasized is that in which
A1 and A2 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or a bond,
A3 and A4 are identical or different and are 1,4-piperazinylene, 1,4-piperidinylene, 1,4-cyclohexylene, 1,3-phenylene or a bond,
A5 and A6 are identical or different and are xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94 or xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94,
M is the following central building block 
K1 is xe2x80x94B7-(C(O))mxe2x80x94B9-Y1 or xe2x80x94B7-(C(O))mxe2x80x94B9-Z1-B11-X1
K2 is B8-(C(O))pxe2x80x94B10-Y2 or xe2x80x94B8-(C(O))p,xe2x80x94B10-Z2-B12-X2,
B1 and B2 are identical or different and are a bond or methylene,
B3, B4, B5 and B6 are identical or different and are a bond or 1-3C-alkylene,
B7, B8, B9 and B10 are identical or different and are a bond or 1-4C-alkylene,
B11 and B12 are identical or different and are a bond or methylene,
m is 0,
p is 0,
X1 and X2 are identical or different and are selected from the following groups 
Y1 and Y2 are imidazol-1-yl,
Z1 and Z2 are identical or different and are 5,2-pyridinylene, 6-methyl-5,2-pyridinylene, 4,1-piperidinylene, 3,6-indazolylene, 3,6-indolylene, 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or 1,4-cyclohexylene,
and where on the direct route between the terminal nitrogen atoms 20 to 40, preferably 25 to 40, bonds have to be present,
the salts of these compounds, and also the N-oxides of the nitrogen-containing heteroaryls, heteroarylenes and heterocycloalkylenes, and their salts, where all those compounds are excluded in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 may assume the meaning of a bond, resulting in the direct linkage of two heteroatoms or carbonyl groups.
Preferred compounds of the formula I are those in which
xe2x80x94B1-A1-B3-A3-B5-A5- and xe2x80x94B2-A2-B4-A4-B6-A6- are identical or different from 
M is the following central building block 
K1 is xe2x80x94B7-(C(O))mxe2x80x94B9-Z1-B11-X1,
K2 is B8-(C(O))pxe2x80x94B10-Z2-B12-X2,
B7, B8, B9 and B10 are identical or different and are a bond or methylene,
B11 and B12 are methylene,
m is 0,
p is 0,
X1 and X2 are amino,
Z1 and Z2 are identical or different and are 1,3-phenylene or 1,4-phenylene,
and the salts of these compounds.
Particularly preferred compounds of the formula I are
1,5-Bis-{2-[4-[(4-aminomethylbenzylaminocarbonyl)piperazin-1-yl]-2-oxoethyl}-perhydro-1,5-diazocin-2,6-dione;
1,5-Bis-{2-[4-(3-(4-aminomethylphenyl)propionyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dione;
1,5-Bis-{2-[4-(3-(3-aminomethylphenyl)propionyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dione;
1,5-Bis-{2-[4-(2-(4-aminomethylphenoxy)acetyl)piperazin-1-yl]-2-oxoethyl}perhydro-1,5-diazocin-2,6-dione;
and the salts of these compounds.
The compounds of the formula I are constructed from a large number of divalent building blocks (M, A1, A2, A3, A4, A5, A6, B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, Z1 and Z2). In principle they can be synthesized starting with any of these building blocks. If the compounds of the formula I are constructed largely symmetrically, it is favorable to start the synthesis with the central building block M, whereas in the case of predominantly asymmetrical compounds of the formula I a synthesis starting with one of the end groups K1 or K2 may be advantageous.
Here, the building blocks are linked using always the same pattern, known per se to the person skilled in the art.
It Is known to the person skilled in the art that the compounds of the formula I can either be synthe sized building block by building block, or by initially constructing relatively large fragments consisting of several individual building blocks, which can then be joined to give the complete molecule.
Owing to the meanings which the individual building blocks of the compounds of the formula I can assume, amino [xe2x80x94NHxe2x80x94], ether [xe2x80x94Oxe2x80x94], thioether [xe2x80x94Sxe2x80x94], keto [xe2x80x94C(O)xe2x80x94], sulfonyl [xe2x80x94S(O)2xe2x80x94], ester [xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94], amide [xe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94C(O)xe2x80x94], sulfonamide [xe2x80x94SO2xe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94SO2xe2x80x94], carbamate [xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94], carbamide [xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94] or carbonate bridges [xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94] are present in the compounds of the formula I.
How to prepare such bridges is known per se to the person skilled in the art; suitable methods and starting materials for their preparation are described, for example, in March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure, Third Edition, 1985, John Wiley and Sons.
Ether and thioether bridges can be prepared, for example, by the method of Williamson.
Keto bridges can be introduced, for example, as a component of relatively large building blocks, such as, for example, 1,3-dichloroacetone.
Sulfonyl bridges can be obtained, for example, by oxidation of thioether bridges.
There is a large number of known methods for preparing ester bridges. An example which may be mentioned here is the reaction of acids with alcohols, preferably using H2SO4 or p-toluenesulfonic acid as catalyst; or with addition of a dehydrating agent, such as, for example, molecular sieve or a carbodiimide. Furthermore, the reaction of acyl chlorides with alcohols may be mentioned here.
There is also a large number of known methods for preparing amide bridges. An example which may be mentioned here is the reaction of acyl chlorides with primary or secondary amines. Furthermore, reference is also made to all the methods which have been developed for peptide chemistry. Accordingly, it is possible to construct sulfonamide bridges from sulfonyl chlorides and primary or secondary amines.
Carbamate bridges can be prepared, for example, by reacting chloroformates with amines. The chloroformates for their part can be synthesized from alcohols and phosgene. A further variant for constructing carbamate bridges is the addition of alcohols to isocyanates.
Similarly to the carbamate bridges, it is possible to prepare carbonate bridges starting from chloroformates, by reaction with alcohols (instead of amines).
Carbamide bridges can be prepared, for example, by reacting isocyanates with amines.
The preparation of compounds of the formula I may be shown in an exemplary manner using the reaction scheme below. Other compounds of the formula I can be prepared analogously, or by using the abovementioned methods known per se to the person skilled in the art. 
Reaction scheme 1 shows an example of the synthesis of a compound of the formula I.
It is also possible to convert compounds of the formula I by derivatization into other compounds of the formula I. Thus, for example, compounds of the formula I having a nitrogen-containing heteroaryl, heteroarylene, heterocycloalkyl or heterocycloalkylene building block can be converted by oxidation into the corresponding N-oxides.
The N-oxidation is carried out in a manner which is likewise known to the person skilled in the art, for example using hydrogen peroxide in methanol or m-chloroperoxybenzoic acid in dichloromethane at room temperature. Which reaction conditions are required in the particular case for carrying out the process is known to the person skilled in the art owing to his expert knowledge.
It is furthermore known to the person skilled in the art that if there are a number of reactive centers on a starting material or intermediate, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center. A detailed description of the use of a large number of proven protective groups is found, for example, in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.
The isolation and purification of the substances according to the invention is carried out in a manner known per se, for example by distilling off the solvent under reduced pressure and recrystallizing the resulting residue from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent (for example a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low-molecular-weight aliphatic alcohol, such as ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by alkalization or by acidification into the free compounds, which in turn can be converted into salts. In this way, pharmacologically unacceptable salts can be converted into pharmacologically acceptable salts.
The examples below serve to illustrate the invention in more detail without restricting it. Likewise, further compounds of the formula I, whose preparation is not explicitly described, can be prepared in an analogous manner or in a manner familiar per se to the person skilled in the art using customary process techniques.
In the examples below, the abbreviation RT stands for room temperature, h for hours, min. for minutes, DMF for dimethylformamide and HBTU for O-(benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexa-fluorophosphate. The compounds mentioned in the examples and their salts are the preferred subject of the invention.